A Practical Approach for Cleaning Validation

the protocol and documentation procedures are varied from company to company but the acceptence criteria is same if both the companies are under same regulatory authorities.If the regulatory authority varie than acceptence criteria alsa varie.

Refrence:Health Products and Food Branch Inspectorate
Good Manufacturing Practices - Cleaning Validation Guidelines.
Date issued:
2000-05-01
Date of implementation:
2000-05-01

thank you

Typical acceptance criteria varied from drug to drug because safety factor and LD 50 values varied from parental to non parental route for the same drug.

Typical acceptance criteria is calculated by using the formula

MACO= (ADI X B)/(LDD)

MACO=maximum allowable carry over
ADI=acceptable daily intake
B=smallest batch size of any product made in same equipment
LDD=largest normal daily dosage of any product made in same equipment.

ADI= (NOEL) / (safety factor)

NOEL= LD50 X 0.0005

NOEL= no observed effect level.

DOSAGE FORM SAFETY FACTOR
Oral dosage form (tab,cap,caplets) 1/1000 to 1/5000 of its daily dose
Topical dosage form (ointments, creams) 1/100 to 1/1000 of its daily dose
Intravenous products 1/5000 to 1/10000 of its daily dose
Ophthalmic products 1/100 to1/5000 of its daily dose

toyal residue is calculated by using the formula
total residue=residue for sq.inch of swab X total surface area

Refrence: Nash and Wacher “pharmaceutical process validation” 3rd edition 2005,pg no 493 and 495-497.

compression of placebo tablets has been shown to be an effective method for removing the residues from the punches and dies. Removal of dyes from blenders and removal of residues from encapsulation machines are done by using placebos.

Factors to be considered for selection of placebo include manufacturability, solubility of components being studied and accurate simulation.

Reference: R. Berry and Robert A. Nash “pharmaceutical process validation” 2nd edition, pg no 327 and 329-330.

“Validation is a process of demonstrating, through documented evidence, that a process, procedure, method, piece of equipment, or facility will consistently produce a product or result that meets predetermined specifications and quality attributes.”

Validation is the scientific study of a system

 To prove that the facility/system/equipment/method is consistently doing what it is supposed to do (i.e., that the process is under control).

We want to make decisions based on good science and not hunches and assumptions!
 To determine the process variables and acceptable limits for these variables, and to set-up appropriate in-process controls.

Advantages of swab method:

-Direct sampling of surface.
-volume of solvent required is less than compared to rinse wash method.
-possibility of complete extraction from the surface.
-cost effective
-development of appropriate analytical methodology may be facilitated by use of appropriate solvent.

Reference: R.Berry and Robert A.Nash “pharmaceutical process validation” 2nd edition, pg no 336-337.

Biological validation comprises of validation of synthetic and olegonucleotides,peptides and plasamides,trangenic proteins,monocolonal antibodies,gene therapy vectors.
Before a biological validation process wa have to evoluate the inherent risk factors associated with product source,raw materials and processing operations.

Refrence: Nash and Wacher “pharmaceutical process validation” 3rd edition 2005,pg no 213.

1.The validation programe is varied from class100 area to class10000 area
The class 100 area is divided into individual grids of each 2ft X 2ft the samples are collected from each and every grid.
The class10000 area also divided into grids of each having higher surface area than compared to class 100 area grids and samples are collected from each grid.
The total no of samples collected is more for class100 area than compared to class 10000 area

Refrence:carleton and agallaco "sterile product process validation"3rd edition,pg no 254.

2.the most commenly used statistical methods in validation are constrain analysis and fractional factorial design.

Refrence: Nash and Wacher “pharmaceutical process validation” 3rd edition 2005,pg no xxv to xxvii.

3. For liquid products either of sterile or non sterile ones water is the best placebo.
For sterile ones water for injection is the placebo
For the drugs which are having a limited solubility in water glycerin is used as placebo

For solid products the residues are removed by abrasion or by physical entrapment here generic solid placebo is used.

Ex; compression of placebo tablets has been shown to be an effective method for removing the residues from the punches and dies. Removal of dyes from blenders and removal of residues from encapsulation machines are done by using placebos.

Factors to be considered for selection of placebo include manufacturability, solubility of components being studied and accurate simulation.

Reference: R. Berry and Robert A. Nash “pharmaceutical process validation” 2nd edition, pg no 327 and 329-330.

4. Validation protocol is prepared by user department (microbiology and production people).
Validation protocol is verified and approved by quality assurance people.
Validation protocol is checked by production people.

Reference: Berry and Harpaz “validation of active pharmaceutical ingredients” 2nd edition pg no 425.

6.The section CFR211.67 indicates the equipement cleaning and its validation as per cGMP and section CFR211.113 indicates the microbial contamination.

Clean room for parental area is validated for two things one for viable and second for non viable ones.

Settle plate techineque, slit air sampler technique, Anderson sampling technique are used for viable organisms.
Electronic devices such are ROYCO particle counter is used for non viable ones.

Reference: J. turco “sterile dosage forms” 4th edition,1994,pg no 40-41

Typical acceptance criteria varied from parental to non parental products because safety factor and LD 50 values varied from parental to non parental route for the same drug.

Typical acceptance criteria is calculated by using the formula

MACO= (ADI X B)/(LDD)

MACO=maximum allowable carry over
ADI=acceptable daily intake
B=smallest batch size of any product made in same equipment
LDD=largest normal daily dosage of any product made in same equipment.

ADI= (NOEL) / (safety factor)

NOEL= LD50 X 0.0005

NOEL= no observed effect level.

DOSAGE FORM SAFETY FACTOR
Oral dosage form (tab,cap,caplets) 1/1000 to 1/5000 of its daily dose
Topical dosage form (ointments, creams) 1/100 to 1/1000 of its daily dose
Intravenous products 1/5000 to 1/10000 of its daily dose
Ophthalmic products 1/100 to1/5000 of its daily dose

Table; safety factor levels for various dosage forms

Refrence: Nash and Wacher “pharmaceutical process validation” 3rd edition 2005,pg no 493 and 495-497.

validation techniques are varied from parental to oral section why because in addition to residues of API,excipients,cleaning agents the parental mfger focus special attention towards end toxins, biobardens,disinfectants,sanitizing agents ,additional possible residues .Rodac plate technique is used for biobardens.

Reference: Nash and Wacher “pharmaceutical process validation” 3rd edition 2005,pg no 501

if cleaning validation is failed that particular instrument or equipement is not allowed for further proceedings such are batch processings etc.that particular instrument or equipement is revalidated.

Reference: R.Berry and Robert A.Nash “pharmaceutical process validation” 2nd edition.

3.Validation protocol is prepared by user department (microbiology and production people).
Validation protocol is verified and approved by quality assurance people.
Validation protocol is checked by production people.

Reference: Berry and Harpaz “validation of active pharmaceutical ingredients” 2nd edition pg no 425.

4.What parameters shall be studied during cleaning process:
At what point does a piece of equipment become clean?
What does visually clean mean?
Does the equipment need to be scrubbed by hand?
What is the most appropriate solvent or detergent?
What is the temperature of solvent used?
What quantity of solvent is used for cleaning?
Are different cleaning processes required for different products in contact with a piece of equipment?
How many times need a cleaning process be applied to ensure adequate cleaning of each piece of equipment?
Reference: Nash and Wacher “pharmaceutical process validation” 3rd edition 2005

hi shoba

1. the procedures were clearly explained in the ppt itself.

the Graduates or Post graduates in microbiology.

2.based on the dirty hold time and clean equipement hold time the revalidation procedures are decided.the def of dirty hold time and clean equipement hold time are provided in ppt itself.

3.in any validation the Q.A people plays an vital role in cleaning validation team comprises of Q.A.

4.the protocol was provided in ppt

is there any doudts please contact us.

thank you.

hi madhu

based upon the complications of the equipment construction the cleaning techniques selected . If the construction is too complicated to swab the interior of the euipment then we go for rinse wash method. if the the instrument is too easy to wash then swab technique is selected.

Refrence:Health Products and Food Branch Inspectorate
Good Manufacturing Practices - Cleaning Validation Guidelines.
Date issued:
2000-05-01
Date of implementation:
2000-05-01